Targeted delivery of botulinum toxin for the treatment and prevention of trigeminal autonomic cephalgias, migraine and vascular conditions

ABSTRACT

Botulinum toxin, among other presynaptic neurotoxins is used for the treatment and prevention of migraine and other headaches associated with vascular disorders. Presynaptic neurotoxins are delivered focally, targeting the nerve endings of the trigeminal nerve, the occipital nerve and the intranasal terminals of the parasympathetic fibers originating in the Sphenopalatine ganglion. The administration preferably targets the extracranial nerve endings of the trigeminal nerve in the temporal area, the extracranial occipital nerve endings in the occipital area, and the intranasal terminals of the trigeminal nerve and parasympathetic fibers originating in the Sphenopalatine ganglion. The delivery is carried out by way of injection or topically.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.12/642,545, filed Dec. 18, 2009, now U.S. Pat. No. 8,241,641,incorporated herein by reference in its entirety, which is acontinuation of U.S. Pat. No. 7,655,244, incorporated herein byreference in its entirety, which claims the benefit of U.S. ProvisionalApplication No. 60/593,641, filed Feb. 1, 2005 and which is alsoincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Migraine is a primary headache disorder that may be characterized byunilateral throbbing pain which worsens with head movement. This can beassociated with other symptoms including nausea, light and noisesensitivity, lacrimation, nasal congestion, and rhinorrhea. An array offactors can trigger migraine headache, such as internal changes(hormonal changes, stress, sleep deprivation) or external changes(weather changes, alcohol, flickering light).

In some cases, a migraine attack begins with a premonitory visual aura.These patients experience a visual disturbance in the form of a zigzagspectrum around a blind spot, which grows in size over a 20-30 minperiod. This visual effect is known as the “fortification spectrum.” Thedevelopment of the fortification spectrum over time has been shown tocorrespond to a wave of depression in the activity of cortical neurons,which typically begins in the occipital lobe, and spreads anteriorly.The establishment of this correspondence has permitted the elaborationof a theory about the pathophysiological changes that may cause migraineand other headaches.

As neurons depress, they release nitric oxide (NO), which triggers thedilation of meningeal blood vessels. This vasodilation can result in 3:dull headache, which corresponds to the earliest phase of migraine.

The dilation of the meningeal blood vessels increases the activity ofthe nerve endings of the primary afferent neurons of the trigeminalnerve that are wrapped around them. As a result, the trigeminal cellsrelease calcitonin gene related protein (CGRP), a vasodilatorneuropeptide which further increases the dilation of the meningeal bloodvessels, and further feeds into the trigeminal nerve activation. Thelocal intracranial increased activation of the trigeminal nerve spreadsthrough the trigeminal ganglion into the Trigeminal Nucleus Caudalis(TNC) in the brainstem in a process known as peripheral sensitization.The activation of the TNC leads in turn to a central activation process,through its thalamic and cortical projections, which are illustrated inFIG. 1.

Although the pain associated with migraine involves input from meningealarteries, activation of the TNC may result in referred pain anywherealong the trigeminal network, including the temporal arteries andtemporal muscles. The trigeminocervical network involved in thepathophysiology of migraine contains the three main branches of thetrigeminal nerve: the ophthalmic branch (V1), the maxillary branch (V2),and the mandibular branch (V3), as illustrated in FIG. 2; as well as thesensory nerves for the posterior head and neck (C2, C3, C4, C5) thatfeed into the TNC. A detailed anatomical map of the relevant pathwayscan be found in pages 316, 317, 600, 601 and 736 of Agur, A. M. R. andDalley II, A. F. (2005) Atlas of Anatomy 11^(th) Ed., LippincotttWilliams & Wilkins, Philadelphia, which is hereby incorporated byreference.

The activation of the TNC in the brainstem can further spread to theoccipital nerve by virtue of its anatomical connection to the TNC,leading to pain sensation in the occipital area. The activation of theTNC can also spread to the parasympathetic system, by activation of anearby nucleus in the brainstem, the Superior Salivatory Nucleus (SSN),which is connected to the nucleus caudalis through a network ofinterneurons, as shown in FIG. 3.

Neurons from the SSN synapse with the Sphenopalatine ganglion, whichprovides vasomotor innervation to blood vessels and secretomotorinnervation to the lacrimal glands, nasal and sinus mucosa. When theparasympathetic system is activated, the upper respiratory tractsymptoms associated with migraine occur including, potentially, nasalsymptoms (rhinorrhea, and post nasal drip), ocular symptoms(conjunctival injection, and tearing) and sinus congestion (pain orpressure around the sinuses). Other parasympathetic projections furtheraggravate the cascade of events, like the Sphenopalatine ganglionafferents that innervate the meningeal blood vessels. Activation of theparasympathetic system during a migraine attack is also accompanied by asignificant increase in the levels of Vasoactive Intestinal Polypeptide(VIP), a parasympathetic neurotransmitter which causes vasodilation andcan be measured in high concentrations during a migraine in the jugularvenous drainage.

The increased activity of the trigeminal, occipital and parasympatheticsystems just described is common to the so-called Trigeminal AutonomicCephalgias (T AC), which include Cluster headache, ParoxysmalHemicrania, SUNCT Syndrome, and Hemicrania Continua. Cluster headachesare a primary headache disorder involving attacks of less than 3 hoursof duration with severe unilateral peri-orbital and temporal pain. Theseheadaches can be associated with lacrimation, nasal congestion,rhinorrhea, conjunctival injection and a Horner's syndrome. The attacksoccur in distinct clusters. Cluster headaches typically involve a seriesof disabling attacks on a daily basis lasting for months at a time. Thispattern recurs annually or biannually.

Paroxysmal hemicrania is a primary headache disorder involving frequentattacks of unilateral, peri-orbital and temporal pain typically lastingless than 30 minutes. The pain can be associated with conjunctivalinjection, lacrimation, nasal congestion, rhinorrhea, ptosis and eyelidedema.

SUNCT Syndrome is a primary headache disorder characterized by multipleattacks of unilateral, peri-orbital and temporal pain typically lastingless than 2 minutes. The pain is associated with conjunctival injection,lacrimation, nasal congestion, rhinorrhea, and eyelid edema. Thisheadache may be associated with trigeminal neuralgia.

Hemicrania Continua is a primary headache disorder characterized by astrictly unilateral headache responsive to Indomethacin. The pain isassociated with conjunctival injection, lacrimation, nasal congestion,rhinorrhea, ptosis, and eyelid edema.

The trigeminal nerve is involved in the pain sensations for all of theseheadache types, as well as headaches triggered by other pathologies. Forexample, Temporal Arteritis involves inflammation of the temporal arterywith painful palpable nodules along the artery. In addition to headachein the temporal area, Temporal Arteritis causes vision loss and jawpain.

Headaches can also be associated with ischemic stroke. In a stroke, alack of blood supply to brain tissue causes a sudden localizedneurological deficit. In a large number of affected patients, occlusionof the arteries is due to the presence of atherosclerotic plaques in thearteries supplying the brain, for example, the carotid artery and thevertebral basilar artery. The atherosclerotic plaques are oftenassociated with inflammation which further contributes to occlusion ofthe blood vessel.

Nociceptive fibers stimulated by inflammatory mediators in infectious orallergic rhinitis can also activate the trigeminal brainstem nucleus andprecipitate migraine.

TAC and Migraine are difficult to treat. Numerous medications have beenused to prevent Cluster and Migraine headaches from occurring, whichinclude, amongst others: Propranolol, Timolol, Divalproex Sodium,Topiramate, Verapamil, Indomethacin and Amitriptyline. These medicineshave numerous side effects and patients are poorly compliant with them.In the case of T AC, Indomethacin, in particular, is difficult forpatients to tolerate due to gastro-intestinal upset.

All of the headache disorders described above produce disability andbetter treatment modalities are needed.

Recently, Botulinum toxin has been shown to be effective to treatmigraine headaches when injected in the face, cranium and neck (Binder,U.S. Pat. No. 5,714,468). Botulinum toxin is a potent polypeptideneurotoxin produced by the gram positive bacterium Clostridium botulinumwhich causes a paralytic illness in humans termed Botulism. Botulinumtoxin has a light and a heavy chain. The heavy chain attaches to a cellsurface receptor and the complex is then endocytosed. After endocytosis,the light chain translocates from the endosome into the cytoplasm, whereit cleaves a segment of the SNARE protein complex responsible forvesicle fusion in the presynaptic nerve terminal. As a result, therelease of neurotransmitters from these vesicles is effectively blockedfor 3-6 months.

There are 7 immunologically distinct toxins: A, B, C₁, D, E, F and G(Simpson, et al., Pharmacol. Rev., 33:155-188, 1981). These toxins bindto presynaptic membranes of target nerves and appear to work in asimilar fashion (Brin, et al., “Report of the Therapeutics andTechnology Assessment Subcommittee of the American Academy ofNeurology”, Neurology, 40:1332-1336, 1990). Botulinum toxin shows a highaffinity for cholinergic neurons. Botulinum toxin A produces areversible, flaccid paralysis of mammalian skeletal muscle, presumablyby blocking the exocytosis of acetylcholine at peripheral, presynapticcholinergic receptors (Rabasseda, et al., Toxicon, 26:329-326, 1988).However, flaccid muscular paralysis is not necessary to achieve thereduction or prevention of migraine symptomatology. In fact, headachepain reduction may be observed at dosages of presynaptic neurotoxinwhich are lower or higher than dosages required to produce flaccidparalysis of skeletal muscle and without introduction of the neurotoxininto muscle tissue (Binder, U.S. Pat. No. 5,714,468).

Although the molecular basis for the sensation of migraine pain is notclear (Goadsby, et al., N. Eng. J. Med., 346:257-270, 2004), Botulinumtoxin might exert its analgesic effect by blocking the release ofnociceptive and inflammatory agents that are released during migraine,and not by blocking the release of acetylcholine. Because Botulinumtoxin does not act on acetylcholine directly, but on the SNARE proteincomplex that mediates vesicle fusion, the release of other moleculeswhich is also mediated by the SNARE protein complex is also affected bythe toxin (Aoki, Current Medicinal Chemistry, 11:3085-3092, 2004). Infact, studies have shown that Botulinum toxin can also block the releaseof substance P, which is associated with neurogenic inflammation andpain generation (Aoki, Current Medicinal Chemistry, 11:3085-3092, 2004),glutamate, also associated with nociception (Cui, et al., Pain,107:125-133, 2004), epinephrine, norepinephrine, and calcitoningene-related peptide (Aoki, Current Medicinal Chemistry, 11:3085-3092,2004). Botulinum toxin A does not appear to cause degeneration ofnervous or muscular tissue and has been approved for use in certaintherapies by the U.S. Food and Drug Administration.

In addition to Botulinum toxin A, other presynaptic neurotoxins havealso been suggested to be useful for the treatment of migraine, giventhe functional characteristics they share with Botulinum toxin (Binder,U.S. Pat. No. 5,714,468). One of these presynaptic neurotoxins isTetanus neurotoxin, which is produced by Clostridium tetani (DasGupta,et al., Biochemie, 71:1193-1200, 1989), and shows significant sequencehomology with serotypes A and E of Botulinum toxin. In particular,fragment The of the Tetanus toxin, which is obtained by peptidedigestion of the toxin, appears to act peripherally to produce flaccidparalysis (Fedinic, et al., Boll. 1st. Sieroter Milan, 64: 35-41, 1985;and, Gawade, et al., Brain Res., 334:139-46, 1985).

Staphylococcal alpha-toxin has also been suggested for therapeutic use.This toxin stimulates the production in the brain of muscle-relaxingfactor (MRF), which results in reversible, flaccid paralysis of skeletalmuscle (Harshman, et al., Infect. Immun., 62:421-425, 1994).Staphylococcal alpha-toxin may function similarly to Botulinum toxin.Other toxins which cause reversible, flaccid paralysis are theacylpolyamine toxins, which are anticholinergic, presynaptic neurotoxinsproduced in the venom of many invertebrates (Herold, et al.,Anesthesiology, 77:507-512, 1992). For example, toxins AR636 and AG489from spiders Argiope aurantia and Agelenopsis aperta lead to motorinhibition at a dosage of 2 micrograms and sensory inhibition at 7micrograms.

Since the use of presynaptic neurotoxins to treat migraines wasinitially implemented by administering the toxins in the face; craniumand/or neck (Binder, U.S. Pat. No. 5,714,468), the hypothesis about thephysiological changes underlying migraine has been significantlydeveloped. The present invention provides an improvement in thetherapeutic and preventive use of Botulinum toxin, among otherpresynaptic neurotoxins, to treat migraines, T AC and other headachesassociated with vascular conditions by using a new method to administerthese neurotoxins. The improvement is based on the recent theory thathas emerged about the pathophysiological changes triggering theseheadaches, which involves the trigeminal, occipital and parasympatheticsystems and therefore affects the administration sites of the toxins.

SUMMARY OF THE INVENTION

There is a need in the medical field to provide an effective therapeuticand prophylactic treatment for migraines, T AC, and other headachesassociated with vascular conditions. The invention provides a method forreducing or preventing symptoms and in particular pain related tomigraines, T AC, and other headaches associated with vascular conditionsin mammals, particularly humans. Specifically, the invention provides animprovement for current methods to treat and prevent these headacheswith presynaptic neurotoxins. More specifically, the present inventionrelates to administering a therapeutically effective amount of apharmaceutically safe presynaptic neurotoxin, peripherally, along theextracranial trigeminal nerve endings in the temporal region, theextracranial occipital nerve endings in the occipital region, as well asalong the intranasal trigeminal nerve endings and parasympathetic nerveendings in the nasal mucosa of a mammal.

The presynaptic neurotoxins of the invention will be those presynapticneurotoxins that produce reversible, localized paralysis of musculaturewhen administered to a mammal (although to practice the invention suchparalysis is not needed) and do not cause degeneration of muscle ornervous tissue. Botulinum toxin, and in particular, Botulinum toxin A isa preferred presynaptic neurotoxin of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. Diagram of headache pain pathways, illustrating the input andoutput pathways of the trigeminal nucleus caudalis in the brainstem.

FIG. 2. Diagram of the trigeminal and parasympathetic network involvedin headache pain, from and into the brainstem.

FIG. 3. Diagram of the neural innervation of the cranial circulation,illustrating the trigeminal nociceptive input from the internal carotidto the trigeminal nucleus caudalis of the brainstem, and the connectionto the parasympathetic system through the superior salivatory nucleus.The parasympathetic system feeds back into the internal and externalcarotids, which connect with the temporal and occipital arteries.

FIG. 4. Illustrated lateral view of a human head showing the connectionbetween the external carotid and the superficial temporal and occipitalarteries. FIG. 4 has been adapted from Agur, A. M. R. and Dalley II, A.F. (2005) Atlas of Anatomy 11^(th) Ed., Lippincottt Williams &Wilkins,Philadelphia. Refer to pages 316, 317, 600, 601 and 736 of the originalreference for a detailed view of the anatomy.

DETAILED DESCRIPTION OF THE INVENTION

The anatomical and physiological theory of migraine, TAC, and otherheadaches associated with vascular conditions, as described in theBackground section, suggests that blockade of the release of nociceptiveand inflammatory agents triggered by the hyperactivation of thetrigeminal, occipital and parasympathetic systems involved in thedevelopment of these headaches should provide an effective therapeuticand/or prophylactic treatment. As FIGS. 1 and 2 show, some of theanatomical pathways involved in the development of these headaches areintracranial; therefore, specific blockade of the intracranial pathwaysinvolved by noninvasive means is not feasible. However, some of thepathways affected are located extracranially under the surface of theskin or intranasally, and are therefore accessible to treatment. Someexamples of these pathways include the temporal arteries and muscles(FIGS. 1 and 4), the nasal glands and mucosa (FIG. 2) and the occipitalnerve and artery (FIG. 4). The current invention relates to providing amethod for blocking the release of nociceptive and inflammatory agentstriggered by the hyperactivation of the trigeminal, occipital andparasympathetic fibers that is increased during migraine, TAC or otherheadaches associated with vascular conditions.

The therapeutic modality used to treat and/or prevent the conditionsdescribed in this patent is the use of presynaptic neurotoxins.“Presynaptic neurotoxin” as used in this disclosure refers to thoseneurotoxins and their derivatives which are known to produce localized,reversible flaccid paralysis of musculature in mammals which does notresult in degeneration of muscle or nervous tissue. However, as statedearlier, flaccid muscular paralysis which the presynaptic neurotoxins ofthe invention will produce is not necessary to achieve the reduction orprevention of headache symptomatology with the method of the invention.

In a preferred embodiment, the presynaptic neurotoxin of the inventionis Botulinum toxin. In a particularly preferred embodiment of theinvention, the presynaptic neurotoxin is Botulinum toxin A. Botulinumtoxin A is presently supplied and commercially available as “Botox”® byAllergan, Inc. of Irvine, Calif., and as “Dysport”® by Ipsen, ofBerkshire, UK. In another embodiment of the invention, the presynapticneurotoxin is Botulinum toxin B. Botulinum toxin B is commercialized as“Neurobloc”®/“Myobloc”® by Solstice Neuroscience, Inc, of San Francisco,Calif. A pentavalent toxoid of all eight known Botulinum serotypes isalso available as an investigational drug from the U.S. Center forDisease Control in Atlanta, Ga. The Botulinum A toxin preparations aremost preferred for their known safety and efficacy. Botox® has also beenused to treat, among other things, cervical dystonia, brow furrows,blepharospasm, strabismus, and hyperhidrosis.

Tetanus toxins are also commercially available for use as vaccines.Since the Ibc fragment of the Tetanus toxin is likely to act in asimilar fashion to Botulinum toxin, as suggested earlier, a furtherembodiment of the invention will preferably comprise the use ofpharmaceutically safe forms of the Ibc fragment of the Tetanus toxinrather than the intact form of the toxin.

Obtaining the presynaptic neurotoxins of the invention, including theBotulinum and Tetanus toxins, in a pharmaceutically safe form andtherapeutically effective amount should be known or easily determined bythose of ordinary skill in the art. The presynaptic neurotoxins shouldpreferably be in a nontetragenic form that does not trigger a detectableimmune response. Pharmaceutical safety will be dose-dependent for mostof the presynaptic neurotoxins of the invention, in such a way thatfairly low doses of toxin will be “safe” as compared to doses known toproduce disease.

The presynaptic neurotoxins of the invention will be preferablyadministered as a composition in a pharmaceutically suitable carrier.For this purpose, presynaptic neurotoxin compositions will be preparedfor administration by combining a toxin of the desired degree of puritywith physiologically suitable sterile carriers. These carriers will notproduce toxic responses in recipients at the doses and concentrationsused. In a preferred embodiment, the preparation of such compositionstypically involves mixing the presynaptic neurotoxin with buffers,antioxidants such as ascorbic acid, low molecular weight (less thanabout 10 residues) polypeptides, proteins, amino acids, carbohydratesincluding glucose or dextrins, chelating agents such as EDTA,glutathione and other stabilizers and excipients. These compositions canalso be lyophilized and will be pharmaceutically acceptable; i.e.,appropriately prepared and approved for use in the desired application.

To facilitate administration, the presynaptic neurotoxins will mostpreferably be formulated in unit dosage form. The presynapticneurotoxins may be supplied, for example, as a sterile solution or as alyophilized powder in a vial.

In general, the amount of presynaptic neurotoxins used for treatmentwill be determined by the age, gender, presenting condition and weightof the patient, in consideration of the potency of the presynapticneurotoxin. The potency of a toxin is expressed as a multiple of theLD₅₀ value for a reference mammal. One “unit” of toxin is the amount oftoxin that kills 50% of a group of mammals that were disease-free priorto inoculation with the toxin. For example, one unit of Botulinum toxinis defined as the LD₅₀ upon intra peritoneal injection into female SwissWebster mice weighing 18-20 grams each. One nanogram of the commerciallyavailable Botulinum toxin A typically contains about 40 mouse units. Thepotency in humans of the Botulinum toxin A product currently supplied byAllergan, Inc. as “Botox”® is estimated to be about LD₅₀=2,730 units.

Assuming an approximate potency of LD₅₀=2,730 units, the presynapticneurotoxin can be administered in a dose of up to about 1,000 units;however, dosages of as low as about 2.5 to 5 units will have therapeuticefficacy. Dosages between 2.5 or 5 units and as high as 250 units willbe normally used, and in a preferred embodiment, individual dosages willbe of about 15-30 units. Typically, the presynaptic neurotoxin will beadministered as a composition at a dosage that is proportionallyequivalent to a range of between 1 cc-5 cc/100 units, which translate to100 units/cc-20 units/cc. Adjustment of these dosages depending on thegreater or lesser potency of the presynaptic neurotoxins and factorsidentified above should be easily determined by those of ordinary skillin the art.

In the preferred embodiment, the dosage used will be the lowest onewhich is still therapeutically effective (i.e., the dosage which resultsin detection by the patient of a reduction in the occurrence and/ormagnitude of headache pain experienced by the patient, even though othersymptoms associated with the pain, such as the premonitory aura, maypersist). The patient's sensitivity to, and tolerance of, thepresynaptic neurotoxin can be determined in the initial treatment, byadministering a low dosage at one site. Additional administrations ofthe same or different dosages can be provided as needed.

The injections will be repeated as necessary. As a general guideline,Botulinum toxin A administered into or near muscle tissue has beenobserved to produce flaccid paralysis at target site muscles for up toabout 3 to 6 months. However, increased efficacy of the treatment usingBotulinum toxin A is expected to happen when the toxin is administeredaccording to the method of the invention at about 3 month intervals.

In a preferred embodiment of the invention, commercially availableBotox® can be reconstituted with sterile non-preserved saline prior toinjection. Each vial of Botox® contains 10 about 100 units ofclostridium Botulinum toxin type A purified neurotoxin complex.Dilutions will vary depending upon the commercial preparation.

The technique of administrating presynaptic neurotoxins to modulate theparasympathetic, trigeminal and occipital nerve responses involved in TAC, migraine and other headaches associated with vascular conditions,involves distributing the presynaptic neurotoxins around the nerveendings involved. Because a high concentration of the trigeminal nerveendings are wrapped around the arteries, injections of presynapticneurotoxins along the trajectory of the temporal extracranial artery isan effective way of administering presynaptic neurotoxins, and inparticular Botulinum toxins, for the treatment of migraine, TAC andother headaches. The same rationale applies to the occipital nerveendings along the extracranial occipital artery. This method helps tolocate the synaptic terminals of the targeted nerves, which allows forthe maximum adherence of presynaptic neurotoxins to the pain generatingnerves involved in headache disorders.

In a preferred embodiment of this invention, the presynaptic neurotoxinsare administered by way of injection. However, in other embodiments, thepresynaptic neurotoxins may be administered topically. In general, thepreparation of the presynaptic neurotoxin solution for topical deliverymay be the same as that which is injected. However, in otherembodiments, the presynaptic neurotoxin may be applied topically via acarrier known to those of skill in the art. The solutions can then beadministered by several means, like for example, a pledget of cotton orcotton tipped applicator, a dropper or a spray in the case of asolution, or a spatula in the case of a cream. These topical methods ofapplication may be used wherever trigeminal, occipital orparasympathetic nerve endings can be accessed efficiently by suchapplication. The solution containing the presynaptic neurotoxins can beadministered topically to the epidermis through these means and thepresynaptic neurotoxins can then be distributed through the epidermis bytransdermal carrier systems. As would be obvious to one of skill in theart, topical administration may not be as effective as administrationvia injection depending on, for example, the patient, the severity ofthe symptoms and access to the trigeminal, occipital and parasympatheticnerves.

The target administration sites for the current invention are theextracranial and intranasal trigeminal nerve endings and parasympatheticnerve endings of the nasal mucosa, the extracranial temporal trigeminalendings and the extracranial occipital nerve endings. Theparasympathetic nerve endings in the nasal mucosa, also situated aroundthe lacrimal glands are illustrated in FIG. 2. The trigeminal nerveendings are situated around the temporal artery (FIG. 4) and temporalmuscle, as shown in FIG. 1, and the occipital nerve endings are locatedaround the occipital arteries (FIG. 4) via cervical nerve roots thatconnect with the trigeminal spinal nucleus. Presynaptic neurotoxinsinjected in these locations every 3-6 months produce a therapeuticbeneficial effect on migraine, TAC and other headaches associated withvascular conditions.

Nasal Administration

To target the intranasal trigeminal nerve endings and parasympatheticnerve endings in the nasal mucosa, the method of administration involvesinfiltrating the upper respiratory tract (nasal mucosa and turbinates)with a presynaptic neurotoxin diluted with a suitable solution such assaline. There is a coalescence of nerve fibers within the upper regionof the nose (intranasally) near the cribiform plate and above thesuperior turbinate. It is also known anatomically that the inferiorturbinate, which is the most responsive organ in the nose, is formed ofbone and mucosa composed of vascular lakes that provide the basis fornasal sprays and topical medications administered intranasally whichprovide for rapid local transmucosal absorption.

In a preferred embodiment, Botulinum toxin Type A (Botox®) is used, andeach nostril is infiltrated with 5 to 10 units using a solution of 100units of Botox® diluted with 4 cc of normal saline. The infiltration inthis preferred embodiment is performed by injection using a 30 gaugeneedle. Intranasal injections are given in each nostril using endoscopicapplication, or a needle palpation technique. The needle is insertedthrough the nostril. Lateral and medial mucosal infiltration isperformed either through finger palpation and guidance or through directvisualization using a nasal speculum and an external light source or viaendoscopic guidance.

In another embodiment, Botox® is used and it is administered in theregion of the external nares using 5 to 10 units using a solution of 100units of Botox® diluted with 4 cc of normal saline. The infiltration inthis preferred embodiment is performed by injection using a 30 gaugeneedle. If necessary, Botox® can be also administered in thedistribution of the infraorbital nerve.

In another embodiment of the invention, infiltration of the presynapticneurotoxins in the upper respiratory tract will be done by topicaladministration to the intranasal mucosa (either alone or with a carriersubstrate) which, because of its anatomical proximity to the endterminals of the trigeminal nerve or the sphenopalatine ganglion thatinnervate the nose, will have a direct effect on the alleviation ofheadache pain. In a particular embodiment, the presynaptic neurotoxinsolution, with or without a carrier, will be delivered with a cottonpledget or a dropper and spread along the targeted area. In anotherembodiment of the invention, the presynaptic neurotoxin solution, withor without a carrier, will be delivered in the form of an emollient,cream or solution, and spread over the epidermis of the targeted area.In yet a different embodiment of the invention, the presynapticneurotoxin solution, with or without a carrier, will be delivered in theform of a spray. Other embodiments may use alternative methods oftopical delivery known to those of skill in the art.

EXAMPLE 1

A 48 yr. old female patient with chronic migraine associated withrhinorrhea and cervical 20 dystonia was treated with the method of thepresent invention. Her migraines involved the left hemicranium and wereassociated with left rhinorrhea. Initial Botulinum toxin treatment usingmigraine and cervical dystonia protocols improved her headaches, but didnot completely abort them, while the rhinorrhea persisted. The patientwas treated with intranasal injections of Botox® 2.5 units (4 ccdilution) four times on the left side only, using the needle palpationapproach. There was no change in the shape of the nose or the cartilagebase. The discomfort was minimal and the bleeding was not excessive. Twoweeks after the treatment, both the rhinorrhea and the headache wereresolved.

Temporal Administration

To target the extracranial trigeminal nerve endings in the temporalregion, the extracranial temporal artery is palpated and the skin ismarked where the artery's pulsations are felt. The area is theninfiltrated with presynaptic neurotoxins diluted in a suitable solutionsuch as normal saline along the course of the artery. In a preferredembodiment, the presynaptic neurotoxin used is Botulinum toxin A, andthe total dose given per artery is 20 units using a solution of 100units of Botox® diluted with 2-4 cc of normal saline. The infiltrationin this preferred embodiment is performed by injection with a 30 gaugeneedle.

In the case of headaches stemming from Temporal Arteritis, presynapticneurotoxins are infiltrated around the temporal artery using a similartechnique to that just described. In a preferred embodiment of theinvention, Botulinum toxin will be administered by injection.

In another embodiment of the invention, infiltration of the presynapticneurotoxins along the temporal artery will be done by topicaladministration, in a similar way as that described for the intranasalarea. In a particular embodiment, the presynaptic neurotoxin solutionwill contain a transdermal carrier. In a different embodiment, thepresynaptic neurotoxin solution will be delivered in the form of a sprayalong the temporal artery, and care will be taken to shield thenon-targeted areas of the scalp.

Occipital Administration

The occipital artery can be treated in a similar fashion. The artery islocated using the following landmarks: the midpoint between the nucalridge (inion) and the mastoid process is found; light palpation is usedto feel the occipital artery's pulse. The hair is separated and the skinis marked along the course of the artery. Presynaptic neurotoxinsdiluted in normal saline or other suitable solution are infiltratedaround each artery. In a preferred embodiment, 20 units of Botox® individed doses are infiltrated around each artery using a solution of 100units of Botox® diluted with 2-4 cc of normal saline. The infiltrationin this preferred embodiment is performed by injection with a 30 gaugeneedle.

In another embodiment of the invention, infiltration of the presynapticneurotoxins along the occipital artery will be done by topicaladministration, in the same way described earlier for the temporaladministration.

Depending on the condition of each patient, the presynaptic neurotoxinswill be administered to one of the sites just described, or to multiplesites. In one embodiment, there are multiple administration sites. In aparticular preferred embodiment, the doses ranging between 25 units and250 units are equally divided among the different administration sites.One of skill in the art should readily ascertain how to adjust thenumber of administration sites and dosages based on individual profilesof weight, gender, age, condition severity and symptoms.

Other Administration Sites

In embodiment of the invention, one can utilize a direct sphenopalatineadministration of presynaptic neurotoxins, which in a preferredembodiment will be Botulinum toxins, and in particular, Botulinum toxinA. In one embodiment, this treatment may follow prior treatments inwhich the presynaptic neurotoxin had been administered at any of theforegoing sites without sufficient results.

In the case of atherosclerotic disease, presynaptic neurotoxins,preferably Botulinum toxins can be injected directly into the plaque viaan intra-arterial catheter. Botulinum toxins will be of benefit as theseplaques produce inflammation in the blood vessel wall in response tocholesterol deposits. This inflammation further compromises the diameterof the lumen of the blood vessel. Botulinum toxins will focally reducethis inflammation for 3 to 6 months.

For the administration of presynaptic neurotoxins by injection, dilutiondependent syringes with gauging for units rather than volume injectedare recommended. This will ensure that the volume injected contains thedesired amount of units, since the volume injected will depend on howthe original concentration of the presynaptic neurotoxin was dilutedwhen reconstituted. For example, in the embodiment in which 100 units ofBotulinum toxin A are reconstituted in 4 cc of normal saline, a specificsyringe with demarcations at 0.1 cc of 2.5 units, and at 0.2 cc of 5units will be used. In another embodiment in which 100 units ofBotulinum toxin A are reconstituted in 1 cc of normal saline, thesyringe with demarcations at 0.1 cc of 10 units; and at 0.2 cc of 20units will be used. These delivery tools allow for accurate delivery andrecording of the dose given.

The invention having been fully described, examples illustrating itspractice should not, however, be considered to limit the scope of theinvention.

What is claimed is:
 1. A method for reducing the occurrence andmagnitude of headache pain in a mammal, wherein mammal has sufferedheadache pain associated with a headache from the group consisting of:migraine, trigeminal autonomic cephalgia and headache caused by avascular condition, comprising administering in a pharmaceutically safeform to a mammal, a therapeutically effective amount of a botulinumneurotoxin type A to nasal parasympathetic nerve endings, therebyreducing the occurrence and magnitude of headache pain in the mammal. 2.The method according to claim 1 wherein the botulinum neurotoxin isadministered by injection.
 3. The method according to claim 1 whereinthe botulinum neurotoxin is a Botulinum toxin complex.